Alzheimer’s Markers Altered With Cancer Drug

The leukemia drug nilotinib (Tasigna) showed hints that it may have disease-modifying benefits in Alzheimer’s disease.
In a phase II study, the drug appeared to be well-tolerated in Alzheimer’s patients but showed more adverse events with higher doses, notably mood swings, reported Charbel Moussa, MBBS, PhD, of Georgetown University in Washington, D.C., and co-authors.
Nilotinib also appeared to alter Alzheimer’s biomarkers. Compared with placebo, central nervous system amyloid burden was lower in the frontal lobe. Cerebrospinal fluid (CSF) Aβ40 was reduced at 6 months and Aβ42 was reduced at 12 months. Hippocampal volume loss was attenuated at 12 months and phospho-tau181 also was reduced at 6 months and 12 months in the nilotinib group, the authors wrote in Annals of Neurology.

“The primary goal of this study was to determine its safety and tolerability in Alzheimer’s patients,” said R. Scott Turner, PhD, MD, director of Georgetown’s Memory Disorders Program and the study’s principal investigator, in a statement. “The study found that it is safe and well-tolerated, as we anticipated, and that it may have disease-modifying benefits.”
“Repurposing nilotinib is not unreasonable, but it is not a benign drug,” noted Ronald Petersen, MD, PhD, of the Mayo Clinic in Rochester, Minnesota, who wasn’t involved with the study. The drug is approved for Philadelphia chromosome-positive chronic myeloid leukemia at 300 mg twice daily and carries a boxed warning for QT prolongation and sudden death.
“The effects in the study were basically on biomarkers; that’s suggestive, but hardly definitive with regard to demonstrating efficacy,” Petersen said in an interview with MedPage Today. “Of course, the study was not designed to look at efficacy, but that’s the million dollar question: if you move these biomarkers, via whatever mechanism, is it going to have a cognitive impact on patients? That’s the big challenge in the field.”

Nilotinib also is being watched closely by the Parkinson’s disease community for possible benefit. A phase II study by the Georgetown researchers suggested it had potential for treating Parkinson’s. This group found it “reasonably safe” in Parkinson’s patients, although the number of serious adverse events rose significantly as the nilotinib dose increased. Other researchers have studied the drug in Parkinson’s disease, however, and concluded that nilotinib did not produce biological or clinically meaningful effects that would benefit Parkinson’s patients.
Nilotinib is a tyrosine kinase inhibitor that targets discoidin domain receptors (DDRs), in addition to the Abelson tyrosine kinase that is its rationale as a cancer drug. In animal models of neurodegeneration, the drug has reduced misfolded proteins. Clinical studies indicate that nilotinib enters the central nervous system, increases dopamine turnover, and reduces CSF tau independent of Abelson inhibition, suggesting nilotinib effects may be mediated by DDR1 inhibition, Moussa and co-authors observed.

The phase II study involved 37 Alzheimer’s patients with mild dementia who were randomized to either placebo or nilotinib. Participants received a 150-mg daily dose of nilotinib or matching placebo orally once daily for 26 weeks, followed by a 300-mg daily dose of nilotinib or placebo for another 26 weeks.
More adverse events, particularly mood swings (agitation and irritation), were seen with the 300-mg dose. Mood swings significantly increased between 6 and 12 months after the dose was upped to 300 mg daily. No QTc prolongation was observed in the nilotinib group versus placebo.
“The current data are in agreement with previous preclinical and other clinical studies at Georgetown suggesting nilotinib is a potential disease-modifying drug that triggers autophagy of neurotoxic proteins including Aβ40, Aβ42, and phospho-tau181,” Moussa said. “The increase in mood swings with 300 mg nilotinib is associated with dose-dependent increases of brain dopamine, suggesting that 150 mg nilotinib is the optimal dosage to investigate in a future Alzheimer’s study.”
The findings will guide the design of a larger, longer phase III study to evaluate nilotinib’s safety and efficacy in people with mild cognitive impairment or Alzheimer’s’s disease, he added.

Disclosures

Funding for the study came from the Alzheimer’s Drug Discovery Foundation, the National Institutes of Health, and the National Center for Advancing Translational Sciences.
Moussa is a named inventor on a portfolio of issued patents and patent applications held by Georgetown and directed to technologies relating to nilotinib, bosutinib, and other drugs. Georgetown University receives Alzheimer’s disease research funding from Roche/Genentech, Lilly, Biogen, Merck, and Acadia.

Primary Source

Annals of Neurology

Source Reference: Turner RS, et al “Nilotinib Effects on Safety, Tolerability, and Biomarkers in Alzheimer’s Disease” Ann Neurol 2020; DOI: 10.1002/ana.25775.

https://www.medpagetoday.com/neurology/alzheimersdisease/86770